It has been observed in the literature that therapeutically effective polypeptides (aan) with two or more amino acids (n≧2) are poorly absorbed orally. Even a polypeptide of as few as two amino acids, or related structures, exhibits very narrow absorption windows and poor bioavailability. As an example, the Physician's Desk Reference (PDR) reports that the angiotensin converting enzyme (ACE) inhibitor Enalaprilat (R1-Ala-Pro; n=2) is very poorly absorbed orally. Enalapril (R2-Ala-Pro), which is a pro-drug of Enalaprilat, is better absorbed orally, but the end result demonstrates only a 25% relative bioavailability of the active moiety (Enalaprilat) released from in vivo cleavage of the prodrug. In comparison, Lisinopril (R3-Lys-Pro) has relatively good solubility in water, but only a moderate oral bioavailability (<25%), with a Tmax (time to maximum serum levels in vivo) of more than seven hours. Thus, this class of therapeutic species is preferably administered via a non-oral deliver method, such as by injection. However, even delivered intravenously, the therapeutically active species has a relatively short serum half-life.
It is also known that some tri-peptides originating in food products may be capable of effective oral absorption, but to an unknown extent. Furthermore, no active tri- or longer peptide drug substances (n≧3) displaying oral absorption have been identified.
In a currently pending U.S. patent application Ser. No. 09/844,426, the disclosure of which is hereby incorporated by reference in its entirety, the present inventors disclosed a method permitting the oral absorption of polypeptide drug substances (aan) and other poorly orally absorbed drugs. We have subsequently made the surprising discovering that additional carrier systems can be effective to achieve similar enhancement of pharmacological activity for poorly absorbed active drug species, and that an optional, more sophisticated linker offers additional improvement in results. Furthermore, we have discovered that, through practice of the methods of the present invention, the length of the polypeptide drug entity (n) can be increased, particularly when the composition is administered parenterally, such as by intravenous (i.v.) administration, with the result of drastically improved pharmacological and therapeutic effects for the active drug moiety. Accordingly, through the practice of the present invention, it is possible to chemically modify a polypeptide species (or, additionally, pseudo-peptides or peptide mimics) of known therapeutic utility to both permit the oral administration of the species and to drastically improve its pharmacological properties even when administered through a parenteral route.
In the present disclosure, the word “peptide” corresponds to any sequence of naturally occurring amino acids, as well as to pseudo-peptides and to peptide mimics. By “pseudo-peptide,” we mean a chemical modification of one or more of the amino acid residues constituting the peptide or of their bonds such as, but not limited to, use of amino acids in their D-configuration, use of N-methyl amino acids, replacement of one or more peptidic bonds (—CO—NH) by a reduced bond (—CH2NH) and/or by —NHCO, —CH2CH2, —COCH2, —CHOHCH2, —CH2O. By “peptide mimic,” we mean any amino acid sequence in which the —C-backbone has been replaced by an oligourea backbone or an oligocarbamate backbone. We also include ω-peptides in this definition.